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Induction of Leukemia-specific Cytotoxic Response by Cross-Presentation of Late-Apoptotic Leukemic Blasts by Autologous Dendritic Cells of Nonleukemic Origin¹

INSERM U419, Institut de Biologie, 44093 Nantes cedex 01, France [R. S., P. C., K. M., M. G.], and Service d’Hématologie Clinique [P. C., N. Mo., N. Mi., J-L. H.] et Laboratoire d’Hématologie Biologique, Institut de Biologie [H. A. L.], Centre Hospitalier Universitaire, 44093 Nantes cedex 01, France

Acute myeloid leukemias (AMLs) are monoclonal proliferations of undifferentiated myeloid progenitors in blood and bone marrow. Long-term remissions are achieved in <50% of patients. There is hope that activation of specific antileukemic immune responses could efficiently eliminate minimal residual disease at the end of chemotherapy and decrease the frequency of relapses. It was demonstrated that AML leukemic blasts can acquire the morphology and phenotype of dendritic cells (DCs), i.e., differentiate into leukemic DCs. However, this method has limitations as a potential immunotherapy. The alternative approach for the induction of leukemia-specific cytotoxicity we explored in this study consisted of using DCs of nonleukemic origin, pulsed with autologous apoptotic leukemic blasts. We show that mature pulsed nonleukemic DCs were successfully generated from remission samples of all tested patients with minimal interindividual differences. Mature pulsed DCs were used as antigen-presenting cells for leukemia-specific CTL induction. Specific cytotoxic activity against autologous AML blasts was demonstrated. Tumor lysis was autologous blast specific, with no killing activity against allogeneic leukemic cells or autologous mature unpulsed DCs and was MHC class I and class II restricted. In one patient, autologous CTLs stimulated by leukemic DCs or pulsed nonleukemic DCs showed similar significant cytotoxic activity against autologous AML cells. These findings demonstrate the induction of leukemia-specific cytotoxic response by nonleukemic mature DCs cross-presenting apoptotic leukemic blasts and offer a complementary approach to the use of leukemic DCs. We believe that this strategy permits the generation of DC vaccines for the majority of patients with hematological malignancies.

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